Pharmacokinetics and Pharmacodynamics of High-Dose Human Regular U-500 Insulin Versus Human Regular U-100 Insulin in Healthy Obese Subjects

• Published in: Diabetes care Vol. 34; no. 12; pp. 2496 - 2501
• Main Authors: de la Peña, Amparo, Riddle, Matthew, Morrow, Linda A, Jiang, Honghua H, Linnebjerg, Helle, Scott, Adam, Win, Khin M, Hompesch, Marcus, Mace, Kenneth F, Jacobson, Jennie G, Jackson, Jeffrey A
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.12.2011
• Subjects: administered dose; Adult; Aged; Area Under Curve; Biological and medical sciences; Blood Glucose - drug effects; blood serum; Clinical medicine; Cross-Over Studies; Diabetes; Diabetes. Impaired glucose tolerance; Dosage and administration; Double-Blind Method; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Female; Glucose; Glucose Clamp Technique; Humans; Hypoglycemic Agents - administration & dosage; Hypoglycemic Agents - pharmacokinetics; Hypoglycemic Agents - pharmacology; Insulin; Insulin resistance; Insulin, Regular, Human - administration & dosage; Insulin, Regular, Human - pharmacokinetics; Insulin, Regular, Human - pharmacology; Life sciences; Male; Medical sciences; Metabolic diseases; Middle Aged; Miscellaneous; Obesity; Obesity - drug therapy; Original Research; patients; Pharmaceutical industry; pharmacokinetics; Public health. Hygiene; Public health. Hygiene-occupational medicine; Statistical methods; subcutaneous injection; therapeutics; Indiana; United States; Human; Obesity; Healthy subject; Nutrition; Insulin human; Nutrition disorder; Metabolic diseases; Biological activity; Pharmacokinetics; High dose; Endocrinology; Nutritional status; Comparative study
• ISSN: 0149-5992; 1935-5548
• DOI: 10.2337/dc11-0721

OBJECTIVE: Human regular U-500 (U-500R) insulin (500 units/mL) is increasingly being used clinically, yet its pharmacokinetics (PK) and pharmacodynamics (PD) have not been well studied. Therefore, we compared PK and PD of clinically relevant doses of U-500R with the same doses of human regular U-100 (U-100R) insulin (100 units/mL). RESEARCH DESIGN AND METHODS: This was a single-site, randomized, double-blind, crossover euglycemic clamp study. Single subcutaneous injections of 50- and 100-unit doses of U-500R and U-100R were administered to 24 healthy obese subjects. RESULTS: Both overall insulin exposure (area under the serum insulin concentration versus time curve from zero to return to baseline [AUC0-t’]) and overall effect (total glucose infused during a clamp) were similar between formulations at both 50- and 100-unit doses (90% [CI] of ratios contained within [0.80, 1.25]). However, peak concentration and effect were significantly lower for U-500R at both doses (P < 0.05). Both formulations produced relatively long durations of action (18.3 to 21.5 h). Time-to-peak concentration and time to maximum effect were significantly longer for U-500R than U-100R at the 100-unit dose (P < 0.05). Time variables reflective of duration of action (late tRmax50, tRlast) were prolonged for U-500R versus U-100R at both doses (P < 0.05). CONCLUSIONS: Overall exposure to and action of U-500R insulin after subcutaneous injection were no different from those of U-100R insulin. For U-500R, peaks of concentration and action profiles were blunted and the effect after the peak was prolonged. These findings may help guide therapy with U-500R insulin for highly insulin-resistant patients with diabetes.